The present invention relates to compounds, their salts, pharmaceutical compositions comprising them, processes for making them and their use in treating Alzheimer""s Disease.
Alzheimer""s Disease (AD) is characterized by the abnormal deposition of amyloid in the brain in the form of extra-cellular plaques and intra-cellular neurofibrillary tangles. The rate of amyloid accumulation is a combination of the rates of formation, aggregation and egress from the brain. It is generally accepted that the main constituent of amyloid plaques is the 4 kD amyloid protein (xcex2A4, also referred to as Axcex2,xcex2-protein and xcex2AP) which is a proteolytic product of a precursor protein of much larger size. The ragged NH2- and COOH-termini of the native Axcex2 amyloid indicates that a complex mechanism of proteolysis is involved in its biogenesis.
The amyloid precursor protein (APP or Axcex2PP) has a receptor-like structure with a large ectodomain, a membrane spanning region and a short cytoplasmic tail. Different isoforms of APP result from the alternative splicing of three exons in a single gene and have 695,751 and 770 amino acids respectively.
The Axcex2 domain encompasses parts of both extra-cellular and transmembrane domains of APP, thus its release implies the existence of two distinct proteolytic events to generate its NH2- and COOH-termini. At least two secretory mechanisms exist which release APP from the membrane and generate the soluble, COOH-truncated forms of APP (APPs). Proteases which release APP and its fragments from the membrane are termed xe2x80x9csecretasesxe2x80x9d. Most APPs is released by a putative xcex1-secretase which cleaves within the Axcex2domain (between residues Lys16 and Leu17) to release (xcex1-APPs and precludes the release of intact Axcex2. A minor portion of APPs is released by a xcex2-secretase, which cleaves near the NH2-terminus of Axcex2 and produces COOH-terminal fragments (CTFs) which contain the whole Axcex2 domain. Finding these fragments in the extracellular compartment suggests that another proteolytic activity (xcex3-secretase) exists under normal conditions which can generate the COOH-terminus of Axcex2.
It is believed that xcex3-secretase itself depends for its activity on the presence of presenilin-1. In a manner that is not fully understood presenilin-1 appears to undergo autocleavage.
The potential of xcex3-secretase inhibitors to inhibit the functioning of presinilins, which have been proposed as candidates xcex3-secretases, has raised questions over their suitability. In particular, signalling through the Notch pathway, important during embryonic development and in haematopoeisis, requires the presenilin-dependent proteolytic release of the Notch intracellular domain (NICD). Using a novel Xenopus developmental assay for Notch activity it has surprisingly been found that the present xcex3-secretase inhibitors do not prevent Notch signalling in-vivo.
The present compounds are structurally related to those disclosed in WO-A-9822494. However there is no discussion in that document of the problem of interference of Notch signalling nor any suggestion of how the provision of xcex3-secretase inhibitors that do not inhibit Notch signalling may be achieved.
Accordingly, the present invention provides a compound of formula I or a pharmaceutically acceptable salt thereof: 
wherein: X is CH2, oxygen or sulphur; and
Ar is phenyl optionally substituted by one, two or three substituents chosen from halogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, hydroxy, cyano, nitro, NR1R2 where R1 and R2 are independently hydrogen or C1-6alkyl, C1-6alkoxy, C2-6alkenyloxy, C2-6alkynyloxy, thiol, C1-6alkylthio, C2-6alkenylthio, C2-6alkynylthio, C1-6alkylcarbonyl, C1-6alkoxycarbonyl, C1-6haloalkyl, C2-6haloalkenyl and C2-6haloalkynyl.
Preferably X is oxygen.
Preferably Ar is optionally substituted by one, two or three substituents chosen from halogen, C1-6alkyl, hydroxy, amino, C1-6alkoxy, thiol, C1-6alkoxycarbonyl and C1-6haloalkyl.
More preferably Ar is optionally substituted by one substituent chosen from halogen, C1-4alkyl, hydroxy, amino, C1-4alkoxy, thiol, C1-4alkoxycarbonyl and C1-4haloalkyl.
In one embodiment Ar is unsubstituted.
A specific Example of the present invention is: 2-[2-(3,5-difluorophenyl)acetylamino]-N-{phenyl[(4-phenylmorpholin-2-ylmethyl)carbamoyl]methyl}propionamide and the pharmaceutically acceptable salts thereof.
As used herein, the expression xe2x80x9cC1-6alkylxe2x80x9d includes methyl and ethyl groups, and straight-chained and branched propyl, butyl, pentyl and hexyl groups. Particular alkyl groups are methyl, ethyl, n-propyl, isopropyl and t-butyl. Derived expressions such as xe2x80x9cC1-4alkylxe2x80x9d, xe2x80x9cC2-6alkenylxe2x80x9d and xe2x80x9cC2-6alkynylxe2x80x9d are to be construed in an analogous manner.
The term xe2x80x9chalogenxe2x80x9d as used herein includes fluorine, chlorine, bromine and iodine, of which fluorine and chlorine are preferred.
As used herein the term xe2x80x9cC1-6alkoxyxe2x80x9d includes methoxy and ethoxy groups, and straight-chained, branched and cyclic propoxy and butoxy groups, including cyclopropylmethoxy. xe2x80x9cC2-6alkynyloxyxe2x80x9d, xe2x80x9cC2-6alkenyloxyxe2x80x9d, xe2x80x9cC1-6alkylthioxe2x80x9d, xe2x80x9cC2-6alkenylthioxe2x80x9d, xe2x80x9cC2-6alkynylthioxe2x80x9d and xe2x80x9cC1-4alkoxyxe2x80x9d are to be construed in analogous manner.
As used herein the term xe2x80x9cC1-6alkoxycarbonylxe2x80x9d includes methoxycarbonyl and alkoxycarbonyl groups and straight-chained, branched and cyclic propoxycarbonyl and butoxycarbonyl groups, including cyclopropylmethoxycarbonyl. xe2x80x9cC1-4alkoxycarbonylxe2x80x9d is to be construed in analogous manner.
Examples of pharmaceutically acceptable salts are hydrochlorides, sulfates, citrates, tartrates, acetates, methanesulfonates, phosphates, oxalates and benzoates.